rs2243266

Variant names:

• chr5-132678097-G-A
• rs2243266
• NM_000589.4:c.184-1617G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000589.4(IL4):​c.184-1617G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 152,110 control chromosomes in the GnomAD database, including 6,592 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (6592 hom., cov: 33)
• Consequence: IL4 NM_000589.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.526
• Publications: 35 publications found

Genes affected

IL4 (HGNC:6014): (interleukin 4) The protein encoded by this gene is a pleiotropic cytokine produced by activated T cells. This cytokine is a ligand for interleukin 4 receptor. The interleukin 4 receptor also binds to IL13, which may contribute to many overlapping functions of this cytokine and IL13. STAT6, a signal transducer and activator of transcription, has been shown to play a central role in mediating the immune regulatory signal of this cytokine. This gene, IL3, IL5, IL13, and CSF2 form a cytokine gene cluster on chromosome 5q, with this gene particularly close to IL13. This gene, IL13 and IL5 are found to be regulated coordinately by several long-range regulatory elements in an over 120 kilobase range on the chromosome. IL4 is considered an important cytokine for tissue repair, counterbalancing the effects of proinflammatory type 1 cytokines, however, it also promotes allergic airway inflammation. Moreover, IL-4, a type 2 cytokine, mediates and regulates a variety of human host responses such as allergic, anti-parasitic, wound healing, and acute inflammation. This cytokine has been reported to promote resolution of neutrophil-mediated acute lung injury. In an allergic response, IL-4 has an essential role in the production of allergen-specific immunoglobin (Ig) E. This pro-inflammatory cytokine has been observed to be increased in COVID-19 (Coronavirus disease 2019) patients, but is not necessarily associated with severe COVID-19 pathology. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Aug 2020]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4	NM_000589.4	c.184-1617G>A		intron_variant	Intron 2 of 3	ENST00000231449.7	NP_000580.1
IL4	NM_172348.3	c.136-1617G>A		intron_variant	Intron 1 of 2		NP_758858.1
IL4	NM_001354990.2	c.284+216G>A		intron_variant	Intron 3 of 4		NP_001341919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL4	ENST00000231449.7	c.184-1617G>A		intron_variant	Intron 2 of 3	1	NM_000589.4	ENSP00000231449.2
IL4	ENST00000350025.2	c.136-1617G>A		intron_variant	Intron 1 of 2	1		ENSP00000325190.3
IL4	ENST00000622422.1	c.284+216G>A		intron_variant	Intron 3 of 4	1		ENSP00000480581.1
IL4	ENST00000495905.1	n.150-1617G>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39131 AN: 151992 Hom.: 6590 Cov.: 33

Gnomad AFR AF: 0.349

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.227

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.257 AC: 39167 AN: 152110 Hom.: 6592 Cov.: 33 AF XY: 0.268 AC XY: 19912 AN XY: 74366

African (AFR) AF: 0.349 AC: 14459 AN: 41466

American (AMR) AF: 0.304 AC: 4642 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 660 AN: 3468

East Asian (EAS) AF: 0.773 AC: 4003 AN: 5178

South Asian (SAS) AF: 0.192 AC: 928 AN: 4828

European-Finnish (FIN) AF: 0.359 AC: 3799 AN: 10572

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10137 AN: 68002

Other (OTH) AF: 0.230 AC: 486 AN: 2112

Alfa AF: 0.175 Hom.: 3514

Bravo AF: 0.263

Asia WGS AF: 0.465 AC: 1617 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.62
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2243266; hg19: chr5-132013789;